Numerous diseases are associated with production of excessive reactive oxygen species (ROS) released by dysfunctional mitochondria, ranging from critical illness to chronic conditions such as diabetes. The prevailing notion is that spleen tyrosine kinase (Syk) is a kinase important for activation of B cells, myeloid cells and other cell of the hematopoietic system. Yet a series of findings suggests that Syk may have additional evolutionarily highly conserved functions in non-hematopoietic tissues. This project will determine whether Syk mediates activation of cellular defense mechanisms such as insulin resistance in response to mitochondrial stressors and excessive ROS release using in vitro and in vivo models. This study would thus implicate Syk as a potential drug target for diabetes and other diseases associated with mitochondrial oxidative stress. The applicant currently holds a joint appointment as research fellow at the Department of Pathology at Brigham and Women's Hospital (BWH) and visiting scientist in the laboratory of Harvey Lodish at Whitehead Institute in Cambridge where she conducts the research that is subject of this proposal. She will be appointed as Instructor of Pathology at Harvard Medical School and Associate Pathologist at the BWH Department of Pathology in Boston in July 2012. Her long-term career goal is to lead an interdisciplinary team of researchers bridging the T1 translational gap at the intersection of inflammation and metabolism. Her immediate goal is to develop a research program revolving around the role of Syk in metabolic tissues, work that will form the basis of grant proposals she intends to submit during the funding period. She will continue to expend a small clinical effort in healthcare management in the BWH clinical laboratories that originated in her third year of residency. In order to achieve her goal, she will attend scientific meetings, seminars, retreats and courses related to her research area and clinical activity as well as take full advantage of the expertise of her mentor and scientific advisors. Whitehead Institute, the site where the proposed research will be conducted, is located in Cambridge, MA with the Massachusetts Institute of Technology, Broad Institute, Massachusetts General Hospital, Harvard Medical School, BWH and the Joslin Diabetes Center nearby. The Whitehead, BWH and the greater Boston scientific community offer ample opportunities for intellectual interactions with other investigators through courses, seminars, and retreats. The Whitehead faculty has trained numerous independent investigators with around 50% of all and 60% of female post-doctoral fellows leaving Whitehead Institute for tenure-track positions in academia. BWH is one of the main teaching hospitals of Harvard Medical School. The BWH Department of Pathology has a strong track record of training young physician scientists having mentored 24 K award recipients since 2003. PUBLIC HEALTH RELEVANCE: Numerous diseases are associated with mitochondrial dysfunction and oxidative stress, ranging from critical illness to chronic conditions such as diabetes. This project explores whether spleen tyrosine kinase (Syk), known for its key role in immune cell activation, promotes activation of cellular defense mechanisms such as insulin resistance in response to oxidative stress. This study may thus provide a rationale for Syk inhibition in the treatment of diabetes and other oxidative stress mediated conditions.